21-fluoro 2-alkyl pregnene compounds



United States Patent ZI-FLUORO Z-ALKYL PREGNENE COMPOUNDS Howard J. Ringoltl and George Rosenkranz, Mexico City, Mexico, assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Aug. 13, 1957, Ser. No. 677,852 Claims priority, application Mexico Aug. 21, 1956 3 Claims. (Cl. 260-3973) The present invention relates to cyclopentanophenanthrene compounds and to a process for the production thereof.

More particularly the present invention relates to novel 21-fiuoro-2-alkyl and 2-aralkyl derivatives and especially to 2l-fiuoro-2-alkyl and 2-aralkyl derivatives of A pregpen-3,20-dione which may be substituted with an a-hydroxyl group at position C-17 and which may also be substituted with an oxygen function (B-hydroxyl or ketone) at position C-ll and to a process for the production of these compounds.

The novel hormones of the present invention having a 17a-hydroxy group as for example ZI-fltlOlO-Zor-EllkYl or aralkyl-A -pregnen-17a-ol-3,1 1,20-tri0ne and 21 -fluoro-2ealkyl or aralkyl-M-pregnen-llB,l7a-diol-3,20-dione are cortical type hormones having anti-inflammatory properties. Compounds of this type cause glycogen deposition in rats. On the other hand, those 2a-methyl-21-fluoropregnene derivatives of the present invention without a hydroxyl group at C-17 are inhibitors of the uterus growth as shownby essays in mice and therefore are anti-estrogenic compounds.

In our U.S. application Serial No. 632,014, filed January 2, 1957, now abandoned, there is disclosed the production of 2-alkyl and Z-aralkyl derivatives of M-pregnene-17a,2l-diol-3,l1,20-trione and of N-pregnene-llfi, l7d,2l-tl'l0l-3,20-dl0fi. By a method precisely similar to that disclosed in the aforementioned application except starting with compounds without the llfi-hydroxy group or the ll-keto group and without the l'la-hydroxy group there may also be prepared similar Z-alkyl and 2- aralkyl derivatives of 2a-alkyl or aralkyl-A -pregnene-21- ol-3,20-dione (2a-alkyl or aralkyl desoxycorticosterone), Za-alkyl or araIkyl-A pregneneJ701,21-diol-3,2O-dione (2a-alkyl or aralkyl Reichsteins Substance S), 2a-alltyl or aralkyl-A pregnene-l 1fl,21-diol-3,20-dione (2rz-alkyl or aralkyl corticosterone), 2a-alkyl or araikyl-M-pregnene-2l-o1-3,11,20-trione (2a-alkyl or aralkyl-ll-dehydrocorticosterone), etc.

In accordance with the present invention it has been discovered that 2ot-alkyl or aralkyl pregnene compounds of the character just described upon treatment with methane sulfonyl chloride in pyridine gave the corresponding 2l-methane sulfonate which when reacted with sodium iodide gave the corresponding 2l-iodo compound. This last intermediate upon reaction with silver fluoride in acetonitrile gave the desired final products namely the 2l-fluoro-2-alkyl or aralkyl derivatives of M-prcgnene- 3,20-dione. The novel compounds of the present invention may therefore be exemplified by the following formula:

fli

In the above formula R represents an alkyl group pref- Patented May 7, 1963 ICC erably a lower alkyl group such as methyl, ethyl or propyl or R may represent an aralkyl group such as benzyl. R represents a hydroxy group in 5 configuration or R represents a keto group or R represents hydrogen. R represents a hydroxy group in a configuration or R represents hydrogen. The novel compounds of the present invention may be prepared by a process exemplified by the following equation:

i 1 s u R" I AgF O 0:

In the above equation R, R and R represent the same groups as heretofore set forth.

In practicing the process of the present invention the Z-alkyl or 2-aralkyl derivative of a A -pregnene-3,2{)-dione is dissolved in a mixture of an organic solvent and pyridine. An especially suitable mixture is chloroformpyridine. The solution is then cooled to below room temperature as for example 0 C. and'rnethane sulfonyl chloride is added thereto in portions. The reaction mixture is then kept at a temperature below room temperature for a period of time of the order of 14 hours. The crude methane snlfonate of the Z-alkyl or aralkyl-M- pregnene-3,20-dione derivative, obtained from the reaction mixture by evaporation to dryness, was then dissolved in organic solvent such as acetone and mixed preferably at room temperature (20 C.) with sodium iodide. The precipitate formed after pouring the reaction mixture into water was the corresponding Za-alkyl or aralkyl-Z'liodo-A -pregnene-3,20-dione derivative. The product was collected by filtration, dried in a vacuum and then dissolved in acetonitrile. Thereafter a solution of silver fluoride in water was slowly added thereto. After a short time silver iodide started to separate leaving in solution the desired 2l-fluoro-2a-alkyl or aralkyl-M-pregnene-E, ZO-dione derivative. The reaction mixture was then allowed to stand at room temperature for about one day and then filtered. The desired 21-fiuoro-2a-alkyl or aralkyLM-pregnene-3.ZO-dione derivative was then obtained from the solution by concentration and crystallization and purified as by recrystallization from an organic solvent such as methyl-acetate.

The following specific examples serve to illustrate but are not intended to limit the present invention.

Example I A solution of 3.4 g. of Za-methyI-M-pregnen-Z1-ol-3,20- dione (2a-methyl-desoxycorticosterone) in 20 cc. of a mixture chloroformpyridine 9:1 was cooled to 0 C. and mixed with 1.4 g. of methanesulfonyl chloride which was added in small portions. The reaction mixture was kept for 14 hours at 0 C. and then it was washed with dilute hydrochloric acid, water and sodium bicarbonate solution and the chloroform was evaporated under vacuum. The residue, consisting of the crude methanesulfonate o-f 2a-methyl-desoxycorticosterone was dissolved in 20 cc. of acetone and treated at room temperature and under stirring with 4 g. of sodium iodide. After decolorizing the mixture by the addition of sodium thiosulfate solution the product was precipitated by the addition of water and the crystalline 2a-methyl-2l-iodo-A -pregnenc-3,20-dione was collected by filtration. The crude product was dried in vacuum, dissolved in 20 cc. of acetonitrile and treated dropwise with 1.4 g. of silver fluoride dissolved in 3 cc. of water. After a short time, silver iodide started to separate leaving the 2-fluoro-2ot-methyl-A -pregnene-3,20-dione in solution. The mixture was kept for 24 hours at room temperature and filtered. Concentration of the filtrate under vacuum gave a crude product which after crystallization from methanolacetone yielded the pure 21-fluoro- 2a-rnethyl-A -pregnene-3,20 -dione or 2-fluoro-2a-methylprogesterone.

Example II By the same method described in Example I, there were prepared: 21-fluoro-2a-methyl-A -pregnen 17o: ol-3,20- dione from 2amethyl-A pregnene-l7u,21-diol-3,20-dione (2a-rmethy1-S); 21-fiuoro-2u-ethyl-A -pregnen-17m-ol-3, 20-dione from 2a-ethyl-A -pregnene-l7a,2l-diol-3,20-dione (2a-ethyl-S); 21-fluoro-2a-benzyl-A -pregnen-17u-ol-3, ZO-dione from 2abenzyl-A pregnene-17x,2l-diol-3,20- dione (2a-benzyl-S); 2l-fluoro-2a-methyl-M-pregnen- 11 3-o1-3,20-dione from 2a-methyl-A -pregnene-11 8,21- diol-3,20-dione (Za-rnethylcorticosterone); 21-flu01'0-2aethyl-M-pregnen-llB-ol-3,20-dione from 20: ethyl-A pregnene-l 1,8,21-diol-3,20-dione (2a-ethyl-corticosterone); 21-fiuoro 2a-benzyl-Mpregnen-11p-ol-3,20-dione from 2:1- benzyl-M-pregnene-l1B,21-diol-3,20 dione (2a benzylcorticosterone) 2-fluo1ro-2ot-rnethyl-A -pregnene-3, 1 1,20- trione from 2a-methyl-A -pregnen-21-ol-3,11,20-trione (2a-methyl-1 l-dehydro-corticosterone) 2 1 -fluoro-2a-ethyl-M-pregnene-SJ1,20-trione from Za-ethyI-A pregnen- 2lol3,11,20-trione (Za-ethyl-l 1-dehydrocorticosterone) 21-fluoro-2u-benzyl-A -pregnene-3,11,20-trione from 2:1- benzyl-A -pregnen-2l-ol-3,11,20-trione (2oc-benzyl-1l-dehydro-corticosterone) 21-fluoro-2a-methyl-A -pregnene- 1 lfi,17a-di0l-3,20-di0118 from 2a-methyl-A -pregnene-1 1,8, 17a,2l-trio1-3,20-dione (2a-methyl-hydrocortisone); 21- fluorO-Za-ethyI-M-pregnene-1 15,17a-diol-3 ,20-dione from 2a-ethyl-A -pregnene-1 1,B,17u,2 1-triol-3,20-dione (Za-ethyl-hydrocortisone) 21-fiuoro-2a-benzyl-A -pregnene-11B, 17a-diol-3,20- dione from 2a-benzyl-A -pregnene-llfl,17a, 21-triol-3,20-dione (2a-benzyl-hydrocortisone); 2l-fluoro- ZwmethyI-M-pregmn-1711-01-3,l1,20-tri-one from 20:- methyl-M-pregnene-17u,21- diol-3 ,1 1,20-trione (Zen-methyl-cortisone) 21-fluoro-2u-ethyl-A -pregnen-17u-o1-3,1 l, 20-trione from Za-ethyl-N-pregnene-17a,21-diol-3,11,20- trione (2a-ethyl-cortisone); and 21-fluoro-2a-benzyl-A pregnen-17u-ol-3,11,20-trione from Za-benzyl-M-pregnene-17a,2l-diol-3,1 1,20-trione (Za-benzyl-cortisone).

We claim:

1. 21-fluorO-Za-methyl-A -pregnen l7aol-3,20-dione.

2. 21-fluoro-2a-methyl-A -3, 1 1,20-trione.

3. A novel compound of the following formula:

CHgF

wherein R is selected from the group consisting of lower alkyl and aralkyl, and R is keto.

References Cited in the file of this patent UNITED STATES PATENTS 2,822,318 Kroll et a1 Feb. 4, 1958 2,865,953 Schneider et a1. Dec. 23, 1958 2,903,449 Fried et al. Sept. 8, 1959 OTHER REFERENCES Hogg et a1.: J.A.C.S. 77, Dec. 5, 1955, pages 6401- 402.

Tannhauser et al.: J.A.C.S. 1956, 78, page 2658. Herz et al.: I.A.C.S. 1956, 78, page 4812. 

3. A NOVEL COMPOUND OF THE FOLLOWING FORMULA: 